CN101896179B - Tape preparation comprising etodolac in ionic liquid form - Google Patents

Tape preparation comprising etodolac in ionic liquid form Download PDF

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CN101896179B
CN101896179B CN2008801202662A CN200880120266A CN101896179B CN 101896179 B CN101896179 B CN 101896179B CN 2008801202662 A CN2008801202662 A CN 2008801202662A CN 200880120266 A CN200880120266 A CN 200880120266A CN 101896179 B CN101896179 B CN 101896179B
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etodolac
tape preparation
ionic liquid
lignocaine
preparation
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CN101896179A (en
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浜本英利
三轮泰司
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MedRx Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
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    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

Disclosed is a tape preparation comprising etodolac in an ionic liquid form, which has high transdermal absorbability. Etodolac is reacted with an organic amine compound to produce an ionic liquid of etodolac. By using the ionic liquid, it becomes possible to increase the transdermal absorbability of etodolac. Further, for the purpose of enhancing the transdermal absorbability and the tissue penetration ability of an ionic solution of etodolac, the composition of an organic solvent system for the ionic solution of etodolac is investigated, and it is found that a mixed solvent of an alcohol and an ester (1:2 to 2:1) is suitable as the organic solvent. Still further, an appropriate adhesion force can be achieved by properly selecting a softening agent. In this manner, a tape preparation having good transdermal absorbability can be prepared. The tape preparation can exert its pharmacological efficacy rapidly, and is therefore extremely effective for the treatment of a chronic pain such as rheumatoid arthritis, osteoarthritis and lumbago, an inflammatory disease such as shoulder periarthritis and tendovaginitis, cervical syndrome, a pain induced by a surgery or an injury, or the like.

Description

The tape preparation that comprises the etodolac of ionic liquid form
Technical field
The present invention relates to comprise the tape preparation (tape preparation) of the etodolac (etodolac) of the ionic liquid form with antiinflammatory and analgesic effect.
Background technology
In the past, known non-steroidal anti-inflammatory drug (Non-Steroidal Anti-Inflammatory Drug) (hereinafter referred to as NSAID) is as anti-inflammatory and analgesic agents.NSAID has by suppressing cyclo-oxygenase (hereinafter referred to as COX) activity that the control prostaglandin relevant to inflammation and/or pain generation generates, and first in described cyclo-oxygenase catalysis metabolic pathway arachidonic acid (arachidonate) cascade reacted and aggravated the pain.
Yet, when when using NSAID and excessively control prostaglandin and produce, because prostaglandin also has multiple effect except producing inflammation or pain, so sometimes report serious side effect.For example, when the COX activity inhibited, phase counterstimulus lipoxygenase is active, and the increase of leukotriene reduces stomachial secretion; The infringement of the active oxygen that while digestive organs mucosa is increased, and produce ulcer.The example of other side effect comprises that renal function is bad, hepatic disfunction, erythra (skin rush) etc., and wherein particularly to bring out aspirin asthma be fatal.
In this case, pour into a large amount of effort and developed the NSAID external preparation with less side effect.By NSAID transdermal delivery to affect position being reduced system's side effect and realizing high levels of drugs at the affect position.
Yet some NSAID have very limited transdermal penetration, and when using as external preparation, drug effect is compared with Orally administered drug effect sharply and reduced.Therefore, propose a kind of externally applied anti-inflammation analgesic compositions that comprises NSAID and local anesthetic, to improve the percutaneous absorbability (patent documentation 1) of NSAID.
Patent documentation 2 also discloses a kind of preparation that comprises as the etodolac of NSAID, and has described when combination lignocaine (lidocaine) and etodolac, has improved the transdermal penetration of etodolac.But what all were were wherein recorded and narrated is the lignocaine of the combination of wide region, and it is 0.1-1.8 mole that its etodolac with 1 mole is compared, and has recorded and narrated the effect of 1.2 moles of lignocaine and 1 mole of etodolac combination in detecting embodiment 1.Therefore, from unexposed mistake characteristic transdermal penetration of the present invention and/or organize penetrating power, the present invention is the tape preparation that comprises etodolac ionic liquid (ambient temperature fuse salt and equimolar lignocaine).
In addition, patent documentation 3 has been described the transdermal penetration of the formation Contrast agent of ionic liquid, but it does not have open when forming the ionic liquid of reagent, and whether the normal compound technology is applicable, says nothing of prediction about the suitable preparation prescription of the ionic liquid of etodolac.
Patent documentation 1:JP2002-128699A
Patent documentation 2:JP2005-239709A
Patent documentation 1:JP2005-82512A
Summary of the invention
The problem that the invention quasi-solution is determined
The problem to be solved in the present invention is to provide a kind of tape preparation that comprises the etodolac ionic liquid, the characteristic that it has very soon fabulous transdermal penetration and show very soon the anti-inflammatory analgetic effect after being applied to skin.
The mode of dealing with problems
Inventor's broad research as the tape preparation about the new formulation of etodolac ionic liquid.As a result, they find, when during as organic solvent, obtaining significant Transdermal absorption effect and splendid tissue permeability with the mixed solvent that forms ionic liquid as the lignocaine of organic amino compounds or triisopropanolamine and suitably select pure and mild ester.In addition, they find how to regulate the adhesiveness of described tape preparation by the selection softening agent, and finally realized the present invention.
The present invention is summarized as follows:
(1) comprise the tape preparation of the ionic liquid of etodolac, it is characterized in that
A) molar salt such as etodolac and lignocaine or triisopropanolamine formation,
B) add organic solvent, wherein pure and mild ester is with 1: 2-2: 1 ratio is mixed, and
C) comprise gelled hydrocarbon as softening agent.
(2) according to above-mentioned (1) described tape preparation, the ionic liquid of wherein said etodolac is the salt of etodolac and lignocaine.
(3) according to above-mentioned (1) or (2) described tape preparation, wherein said alcohol is propylene glycol.
(4) according to the described tape preparation of any one in above-mentioned (1)-(3), wherein said ester is ethyl sebacate.
(5) according to the described tape preparation of any one in above-mentioned (1)-(4), wherein also add vaseline as softening agent.
(6) according to the described tape preparation of any one in above-mentioned (1)-(5), wherein said gelled hydrocarbon is plastibase.
(7) according to the described tape preparation of any one in above-mentioned (1)-(6), wherein comprise the etodolac of 1-5 (w/w) %.
(8) according to the described tape preparation of any one in above-mentioned (1)-(7), wherein said pure and mild described ester adds with identical proportion of composing (w/w%).
(9) according to the described tape preparation of any one in above-mentioned (1)-(8), wherein tackifier resins (tackifier resin) is to be selected from one or more in polybutene, hydrogenated petroleum resin and terpene resin.
(10) according to the described tape preparation of any one in above-mentioned (1)-(9), wherein said tackifier resins is terpene resin.
The invention effect
The tape preparation that comprises the etodolac ionic liquid in the present invention has splendid transdermal penetration and organizes penetrating power, brings into play fast its pharmaceutically active, and also has the good characteristic of sticking.Therefore, described preparation is effective to treat chronic pain, the pain of bringing out as rheumatoid arthritis (rheumatoidarthritis), osteoarthritis (osteoarthritis) and lumbago (lumbago), inflammatory diseases such as periarthritis humeroscapularis (shoulder periarthritis) and tenosynovitis (tendovaginitis), neck syndrome (cervical syndrome), by operation or damage etc.
The best mode that carries out an invention
The example of " alcohol " in the application comprises higher alcohol, as benzyl alcohol, lauryl alcohol, tetradecyl alchohol, hexadecanol, stearyl alcohol, cetearyl alcohol, 2-octyl dodecanol etc., C1-C10 lower alcohol such as ethanol, propanol, isopropyl alcohol, n-butyl alcohol, amylalcohol, capryl alcohol, lauryl alcohol etc., or multivalence alcohol is as ethylene glycol, propylene glycol, 1,3 butylene glycol, Polyethylene Glycol etc.Wherein, ethanol, isopropyl alcohol, ethylene glycol and propylene glycol are preferred.
The example of " ester " in the application comprises ketone such as methylisobutylketone; Low-grade alkyl carboxylate such as ethyl acetate, propyl acetate, ethyl n-butyrate. etc.; Fatty acid ester such as ethyl sebacate, isopropyl myristate, diisopropyl adipate, Palmic acid myristin, stearyl stearate, myristyl myristate, oleic acid triglyceride (oleic acid triglyceride), seryl ceryl cerotate (seryllignocerate), laccerol serolate, lacceroic acid dotriacontane ester (lacceryl laccerylate), carbonic ester such as propylene carbonate (propylene carbonate) and vegetable oil such as olive oil, Petiolus Trachycarpi wet goods.Wherein, fatty acid ester such as isopropyl myristate, ethyl sebacate etc. and vegetable oil such as Petiolus Trachycarpi oil, Fructus Canarii albi wet goods are preferred.
Word " adding proportion of composing is 1: 2-2: the organic solvent of 1 (w/w%) " means above-mentioned pure and mild ester with 1: the proportion of composing scope of 2-2: 1 (w/w%) is mixed and as solvent.Preferably, illustrate 1: 1.5-1.5: the proportion of composing scope of 1 (w/w%), and the proportion of composing of 1: 1 more preferably from about.
In addition, surpass above-mentioned proportion of composing scope (1: 2-2: 1) tend to reduce percutaneous absorbability.For example, when alcohol forms when increasing to the ratio of 4: 1, the percutaneous absorbability of etodolac is reduced to approximately 1/3rd.
About the combination of pure and mild ester, can use above-mentioned any pure and mild any ester, and the example of preferred compositions comprises propylene glycol or ethylene glycol as alcohol, and ethyl sebacate or isopropyl myristate are as ester.Preferred as the propylene glycol of alcohol with combination as the ethyl sebacate of ester.
In the application, " softening agent " means to improve and sticks the additive of thing (adhesive mass) (adhesion layer) characteristic, and usually uses gelled hydrocarbon.In addition, for any purpose, can use oil-extender such as liquid paraffin, vaseline, process oil or low molecular weight polycaprolactone butylene; Fatty oil softening agent such as Oleum Ricini or Petiolus Trachycarpi oil; Or the lanoline of purification.In the present invention, can use the combination of independent gelled hydrocarbon or a class or multiclass softening agent as softening agent.Preferably, the example that is added into the softening agent in gelled hydrocarbon comprises oil-extender such as liquid paraffin, vaseline, process oil or low molecular weight polycaprolactone butylene.More preferably, exemplify liquid paraffin or vaseline.Can also use Plastibase (trade (brand) name) as gelled hydrocarbon.
In the application, " tackifier resins " means to be applicable to any resin of tape preparation, and the example of this resin comprises terpene resin, vistanex, fragrant Petropols, hydrogenated petroleum resin, Colophonium and rosin derivative (for example, Foral).Preferably, exemplify terpene resin (for example, Clearonp-125, YS resin PX-1150N etc.), vistanex (for example, polybutene) and hydrogenated petroleum resin (for example, alcon P-100).Wherein, terpene resin is particularly preferred.Compare with other tackifier resins in preparation, terpene resin has better heat stability, and is difficult to penetrate the backing cloth by the adhesion layer that terpene resin is made.Therefore, the sticking of tape preparation of being made by terpene resin is difficult for being compromised, and these tackifier resins can use separately or two or more tackifier resins is used in combination, and is used for any purpose.
Usually, tape preparation is comprised of elastomer and viscosifier, softening agent, filler, antioxidant etc., and can use in the present invention the composition of any commonly used and extensive use, particularly can randomly add or cancel filler and antioxidant.
the example of above-mentioned elastomer (elastmer) comprises styrene isoprene styrene block copolymer (SIS) (styrene-isoprene-styrene block copolymer) (SIS), styrene butadiene styrene block copolymer (SBS) (styrene-butadiene-styrene block copolymer), styrene-ethylene-butadiene rubber-styrene block copolymer (styrene-ethylene-butadienerubber-styrene block copolymer), SBR styrene butadiene rubbers (styrene-butadienerubber), synthetic rubber such as polyisoprene (polyisoprene), polyisobutylene (polyisobutylene), polybutene (polybutene), butyl rubber and silicone rubber etc., acrylic resin such as polymethyl acrylate (methyl polyacrylate) and polymethyl methacrylate (methylpolymetacrylate), natural rubber etc.Preferred example comprises styrene isoprene styrene block copolymer (SIS), SBR styrene butadiene rubbers and rubber polymer such as polybutene, polyisoprene, butyl rubber and natural rubber etc., and these can use separately or use in the lamination mode of two or more these.
The example of above-mentioned filler comprises zinc oxide, titanium oxide, calcium carbonate, silicic acid etc.
The example of above-mentioned oxidant comprises dibenzylatiooluene (dibutylhydroxytoluene) (BHT), 4,4-dioxydibenze, EDTA-2Na etc.
According to target disease or needs, can comprise the active component etodolac of variable in the present invention.Usually, the example of etodolac content comprises 1-10 (w/w) %.The etodolac that preferably comprises 1-5 (w/w) %.More preferably, the etodolac that comprises 2-3 (w/w) %.
The plaster that the present invention comprises the ionic liquid of etodolac can prepare according to known any method, for example, it can be dissolved in together with excipient such as alcoholic solvent, ester solvent, softening agent or viscosifier etc. by the ionic liquid with etodolac in solvent as toluene, hexane or ethyl acetate etc., remove described solvent by drying after it being spread on release liner or backing, and with another release liner or backing, it is covered at last.
Any backing can be used in plaster of the present invention, for example, any stretching backing or non-stretching backing can be used.The example of backing comprises cloth, nonwoven cloth, polyurethane, polyester, polyvinyl acetate, poly-inclined to one side vinylidene chloride (polyvinylidene chloride), polyethylene, polyethylene terephthalate (polyethylene terephthalate), aluminium flake or its combined material.
In plaster of the present invention, release liner used comprises polyester such as polyethylene terephthalate; Thin film such as polrvinyl chloride or poly-inclined to one side vinylidene chloride; With the laminated film that is formed by quality paper and polyolefin.For the liner that is easy to remove is provided, preferably processes with silicon or fluorine and be adhered to the pad surfaces of sticking the thing layer.
Embodiment
The present invention more specifically sets forth by following work embodiment and detection embodiment, but the invention is not restricted to these embodiment.
Embodiment 1: the ionic liquid and the Transdermal absorption that form etodolac by organic amine compound
By the etodolac of equimolar amounts and organic amine compound are mixed according to the mixed proportion (w/w%) of table 1, the ionic liquid (fuse salt) of preparation etodolac and 80 ℃ of heating.Composition except etodolac is dissolved in respectively in toluene, the ionic liquid of etodolac is added wherein, and mix, to produce uniform solution.The coating machine that is full of described solution by operation prepares tape preparation.That is, at first stripping film (polyester) is used described solution coatings, consequently sticking amount of substance after drying is 100g/m 2, and by drying under heating condition, toluene evaporates is fallen.Backing (non-woven fabrics) is attached to the surface of plaster, cuts whole film to produce tape preparation.
Use the Transdermal absorption of the formed tape preparation of Franz pond (Franz Cell) assessment, and assess Transdermal absorption (the μ g/cm of etodolac after beginning to test two hours 2).These results are presented in table 1.
[table 1]
Detect number With reference to embodiment 1 1 2 3 4
Etodolac 2.4 2.4 2.4 2.4 2.4
Organic amine compound Nothing Lignocaine: 1.96 TEA： 1.20 TIA： 1.60 DIA： 1.10
Organic solvent: propylene glycol ethyl sebacate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0
Antioxidant: BHT 1.0 1.0 1.0 1.0 1.0
Softening agent liquid paraffin white vaseline plastibase 21.6 10.0 10.0 19.64 10.0 10.0 20.0 10.0 10.0 20.5 10.0 10.0 20.4 10.0 10.0
Tackifier resins: polybutene alcon P-100 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0
Elastomer: SIS 12.0 12.0 12.0 12.0 12.0
Total amount 100.0 100.0 100.0 100.0 100.0
Transdermal absorption (μ g/cm 2) 4.5 19.0 1.0 5.2 0.2
[notes]
TEA: triethanolamine
TIA: triisopropanolamine
DIA: diisopropanolamine (DIPA)
The Transdermal absorption that comprises the tape preparation of the etodolac salt (ionic liquid) that is obtained by etodolac and lignocaine or isopropanolamine is better than the Transdermal absorption of the tape preparation that only comprises etodolac.The basicity of organic amine compound is presented in following table 2, and these data show that the Transdermal absorption of etodolac salt also is subjected to the impact of other factors except the basicity affects that is subjected to this organic amine compound, as is subjected to the impact of hydrophobicity etc.
[table 2]
Acidic materials pKa Alkaline matter pKa
Etodolac 4.65 Diisopropanolamine (DIPA) 9.00
Triisopropanolamine 8.03
Lignocaine 7.86
Triethanolamine 7.77
The difference of the pKa value between etodolac and lignocaine is about 3.2, and predicts the mixture that balance is arranged, but by IR and/or H-NMR judgement, confirms that the mixture of etodolac and lignocaine is not equilibrium mixture, but forms salt.Difference by the pKa value never predicts forming of salt.
As above shown in table 1, compare with the percutaneous absorbability without the etodolac of lignocaine, the lignocaine salt of etodolac has the approximately percutaneous absorbability of four times.In addition, in detecting, observe the existence that depends on lignocaine in as the exemplified rat body of detection embodiment 2, the blood level of etodolac increases approximately five times.Therefore, compare with the percutaneous absorbability without the etodolac of lignocaine, confirmed excellent percutaneous absorbability in the tape preparation of the lignocaine salt (ionic liquid) that comprises etodolac.
Embodiment 2: the impact of solvent on the tape preparation of the ionic liquid (with the salt of lignocaine) that comprises etodolac
(1) dissolubility of the lignocaine salt of etodolac
The dissolubility of lignocaine salt (ionic liquid) in organic solvent of estimation etodolac, and attempt controlling percutaneous absorbability by the composition of regulating organic solvent.At first, assessed the dissolubility of lignocaine salt in the organic solvent shown in table 3 of etodolac.
[table 3]
Figure GPA00001157448200091
[notes]
Zero: dissolving
△: part is undissolved
*: undissolved
Due to lignocaine salt indissoluble in softening agent such as liquid paraffin etc. of etodolac, show to add organic solvent with highly dissoluble with the necessity of the precipitation of avoiding etodolac salt in producing tape preparation.
(2) impact of solvent on the percutaneous absorbability of tape preparation
As shown in table 3, the lignocaine salt of etodolac has good dissolubility in pure and mild ester, and the research solvent is on the impact of percutaneous absorbability, as selecting propylene glycol, 1,3 butylene glycol and ethyl sebacate as solubilizing agent.At first, the tape preparation that has the composition (w/w%) of table 4 according to the method preparation of embodiment 1.Then, at percutaneous absorbability (the μ g/cm according to assessment etodolac after detecting embodiment 1 and using the detection that carries out in the Franz pond to begin two hours 2).Result is also shown in table 4.
[table 4]
Detect number With reference to embodiment 2 5 6 7 1 8
Etodolac 2.4 2.4 2.4 2.4 2.4 2.4
Organic amine compound (lignocaine) 1.96 1.96 1.96 1.96 1.96 1.96
Organic solvent: propylene glycol 1,3 butylene glycol ethyl sebacate 0 0 0 4.0 4.0 4.0 2.0 2.0 2.0 2.0
Antioxidant: BHT 1.0 1.0 1.0 1.0 1.0 1.0
Softening agent liquid paraffin white vaseline plastibase 23.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0
Tackifier resins: polybutene alcon P-100 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0
Elastomer: SIS 12.0 12.0 12.0 12.0 12.0 12.0
Total amount 100.0 100.0 100.0 100.0 100.0 100.0
Transdermal absorption (μ g/cm 2) 9.0 8.5 8.5 7.0 19.0 18.0
As table 4 with reference to as shown in embodiment 2 and embodiment 5-7, there is or do not exist organic solvent, percutaneous absorbability is not had much affect, but compare with the situation of using single solvent, observing approximately when having pure and mild ester simultaneously, the percutaneous absorbability of twice increases.
Embodiment 3: the composition of organic solvent changes and on the impact of percutaneous absorbability
Find to exist simultaneously pure and mild ester to promote Transdermal absorption, then by changing the composition of alcohol (propylene glycol) and ester (ethyl sebacate), the best of research solvent forms (w/w%).For this purpose, has the tape preparation of the composition (w/w%) of following table 5 according to the method preparation of embodiment 1.
Use Franz measures in the pond Transdermal absorption of the tape preparation that obtains, and assesses Transdermal absorption (the μ g/cm of etodolac after beginning to test two hours 2).Result also is presented in table 5.
[table 5]
Detect number 5 9 10 1 11 12
Etodolac 2.4 2.4 2.4 2.4 2.4 2.4
Organic amine compound (lignocaine) 1.96 1.96 1.96 1.96 1.96 1.96
Organic solvent: propylene glycol ethyl sebacate 4.0 3.2 0.8 2.7 1.3 2.0 2.0 1.3 2.7 0.8 3.2
Antioxidant: BHT 1.0 1.0 1.0 1.0 1.0 1.0
Softening agent liquid paraffin white vaseline plastibase 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0 19.64 10.0 10.0
Tackifier resins: polybutene alcon P-100 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0 1.0 38.0
Elastomer: SIS 12.0 12.0 12.0 12.0 12.0 12.0
Total amount 100.0 100.0 100.0 100.0 100.0 100.0
Transdermal absorption (μ g/cm 2) 8.5 5.8 10.3 19.0 11.0 6.3
As shown in table 5, when the proportion of composing of alcohol (propylene glycol) and ester (ethyl sebacate) 1: 2-2: in the time of in 1 (w/w%) scope, the increase of the percutaneous absorbability of the lignocaine salt of etodolac.In addition, when alcohol form to increase and the proportion of composing of alcohol (propylene glycol) and ester (ethyl sebacate) when being 4: 1 (No. 9 detections), the percutaneous absorbability of etodolac is reduced to approximately 1/3rd.
Embodiment 4: the impact of softening agent on the adhesion of tape preparation
Think that the adhesion of tape preparation is subject to adding to the amount of the softening agent in adhesion layer (elastomer and viscosifier) and the impact of type.Then, has the tape preparation of the composition (w/w%) of table 6 according to the method preparation of embodiment 1, with the impact of research softening agent on the adhesion of tape preparation.
The tape preparation that obtains is carried out adhesion detect (Ball-tack detection), and result also is presented in table 6.
[table 6]
Detect number 1 13
Etodolac 2.4 2.4
Organic amine compound (lignocaine) 1.96 1.96
Organic solvent: propylene glycol ethyl sebacate 2.0 2.0 2.0 2.0
Antioxidant: BHT 1.0 1.0
Softening agent liquid paraffin white vaseline plastibase 19.64 10.0 10.0 39.64 0 0
Tackifier resins: polybutene alcon P-100 1.0 38.0 1.0 38.0
Elastomer: SIS 12.0 12.0
Total amount 100.0 100.0
Adhesion detect 50 ℃ 3M:1 minute 30 seconds No.8 No.9 No.7 No.7
[notes]
Top rolling diameter by the inclined-plane is the steel ball of 3.2mm (No.1)-15.9mm (No.9), and measures to be bonded in and stick the lip-deep time.The number that shows the maximum gauge of bonding fixed time.
When detecting for No. 1 in table 6 and detecting for No. 13 when comparing, No. 1 detections that comprises white vaseline and plastibase more is added with adhesion than No. 13 detections, and shows and have the intensity that is enough to be used as tape preparation.
In addition, when preserving under stringent condition (50 ℃ 3 months), the adhesion of the tape preparation that detects for No. 1 worsens and is improved.
Embodiment 5: the impact of viscosifier
In order to study as the impact on the Transdermal absorption of reagent of the viscosifier of the substrate of tape preparation, preparation has the tape preparation of the composition (w/w%) of table 7.
The percutaneous absorbability of the tape preparation that obtains is measured according to detecting embodiment 1 in use Franz pond, and has assessed Transdermal absorption (the μ g/cm that begins to test the etodolac after two hours 2).Result also is presented in table 7.
[table 7]
Detect number 1 14
Etodolac 2.4 2.4
Organic amine compound (lignocaine) 1.96 1.96
Organic solvent: propylene glycol ethyl sebacate 2.0 2.0 2.0 2.0
Antioxidant: BHT 1.0 1.0
Softening agent liquid paraffin white vaseline plastibase 19.64 10.0 10.0 26.64 10.0 10.0
Tackifier resins: polybutene hydrogenated petroleum resin (alcon P-100) terpene resin 1.0 38.0 32.0
Elastomer: SIS 12.0 12.0
Total amount 100.0 100.0
Transdermal absorption (μ g/cm 2) 19.0 17.4
As above shown in table 7, the change of viscosifier is very little on the Transdermal absorption impact of etodolac.
As implied above.In detecting, the assessment of Transdermal Absorption observes similar percutaneous absorbability, provide preferred etodolac hematodinamics during but No. 14 tape preparation detects (detection of assessment blood level) in based on the body that detects embodiment 5 use nothing hair rats, its result is presented in Fig. 4.
Because the tape preparation that detects for No. 14 has superior effect, use carrageenin foot pad edema model to carry out the tape preparation that detects for No. 14 and the comparative experiments of other tape preparation (Flector paster).Result as shown in Figure 5, show No. 14 more effective than other tape preparation (Flector paster).
Detect embodiment 1: use Franz pond assessment percutaneous absorbability
About every kind of adhesive tape preparation based on the preparation of the described formula of table 1, use the Franz pond at the transdermal penetration of external assessment etodolac in rat.
The receiving chamber in Franz pond is full of normal saline, and is warmed to 32 ℃.Remove detecting the hair of the previous day with Wister rat (5 age in week) abdominal part, and abdominal part of picking.Skin of abdomen is applied to Franz pond and fixing.Then, on fixing skin, and use Chi Gai to clamp every kind of adhesive tape formulation application.After one hour or two hours, sampling is the tracer liquid of 300 μ l approximately, and uses HPLC (λ: 225nm) analyze.
Detect embodiment 2: the assessment of the blood level in rat detects
Detect the previous day, using electric shear or shaver carefully to remove the hair at male SD rat (4 age in week) the skin back side.Clamp after the zone is not compromised in checking, apply at this back and detect embodiment (No. 1 detect, with reference to embodiment 1 or with reference to embodiment 3), and stick the dressing sealing by nonwoven.After sealing 24 hours, the sample that remove to apply, and with the coated position of absorbent cotton wiping of warm water moistening.Sealing applies the position again, licks in case the stop thing is licked it.In addition, second group of same back an animal applies simultaneously with reference to embodiment 1 and 3, to avoid overlapping.
Result is presented in Fig. 1.The tape preparation that discovery comprises etodolac lignocaine salt (ionic liquid) produces the blood level than high five times of the blood level of the tape preparation that only comprises etodolac.
Detect embodiment 3: detection (1) the preparation test sample of the structure of checking etodolac lignocaine salt (ionic liquid)
A etodolac lignocaine salt:
Equimolar etodolac (2.4g) and lignocaine (1.96g) in approximately 70 ℃ of mixing, and are cooled to room temperature, to produce high viscosity gelatin sample oily matter.
The propylene glycol solution of B etodolac lignocaine salt:
With etodolac (2.4g), lignocaine (1.96g) and propylene glycol (4.4g) 50 ℃ of mixing to produce oily matter.
(2) elementary analysis
As the result of the elementary analysis of the etodolac lignocaine that obtains in above-mentioned A, measured value is corresponding with the value of calculation in table 8.
[table 8]
C(％) H(％) N(％)
About C 31H 41N 3O 4Calculate 71.65 7.95 8.09
Find 71.80 7.86 8.18
(3) measure IR spectrum
Use Fourier transformation IR spectrometer (FTIR-8400S, Shimazu company) to measure the IR absorption spectrum.
The etodolac lignocaine salt of above-mentioned A is very sticking, so that it is dissolved in a small amount of chloroform, is clipped between the NaCl plate, and measures.On the other hand, the PG solution of etodolac lignocaine B is clipped between the NaCl plate and directly measures.In addition, measure respectively each in etodolac and lignocaine in chloroform and propylene glycol (PG), to compare.
Result is presented in following table 9.
[table 9]
Figure GPA00001157448200161
About the IR spectrum of etodolac, in chloroform and PG respectively at 1705cm -1And 1710cm -1The place finds the broad absorption band based on the C=O stretching vibration of free carboxylic acid groups.About lignocaine, it is at 1665-1670cm that the C=O stretching vibration of amidocarbonylation detects -1The broad absorption band at place.
In the situation of etodolac lignocaine, chloroform and in PG all not at 1705-1710cm -1The place observes any peak based on free-COOH.Yet, at 1575cm -1The place observes the IR spectrum of PG solution, namely based on the new absorption band of carboxyl anion (COO-).
(4) measure proton N MR spectrum
Use Fourier transformation 400mHz NMR spectrometer (Ultra Shield 400Plus, Bruker company) to measure proton N MR spectrum.
Each in the etodolac lignocaine salt of above-mentioned A, independent etodolac and independent lignocaine is dissolved in chloroform-d3, and measures NMR spectrum.
Result is presented in table 10 and table 11.
[table 10]
Figure GPA00001157448200171
(A): etodolac-lignocaine
(B): etodolac
[table 11]
Figure GPA00001157448200181
(A): etodolac-lignocaine
(C): lignocaine
IR and NMR spectral measurement support that etodolac and lignocaine are not the mixture of two kinds of compounds, but the salt as the Novel ion liquid compound that forms between etodolac and lignocaine.
With reference to embodiment 3: preparation only comprises the tape preparation of lignocaine
With lignocaine 0.98g, propylene glycol 1.0g, ethyl sebacate 1.0g, BHT 0.5g, liquid paraffin 10.08g, white vaseline 5.0g, plastibase 5.0g, polybutene 0.5g, alcon P-10019.0g and SIS 6.0g are dissolved in toluene, and by preparing tape preparation according to embodiment 1 operation coating machine.
With reference to embodiment 4: preparation only comprises substrate and without the tape preparation of etodolac and lignocaine
With propylene glycol 2.0g, ethyl sebacate 2.0g, BHT 1.0g, liquid paraffin 19.64g, white vaseline 10.0g, plastibase 10.0g, polybutene 1.0g, alcon p-10038.0g and SIS 12.0g are dissolved in toluene, and by preparing tape preparation according to embodiment 1 operation coating machine.
Detect embodiment 4: detect the antiinflammatory or the analgesic effect that comprise the tape preparation of etodolac lignocaine salt (ionic liquid) with checking
(1) detect tape preparation with the assessment of adjuvant arthritis rat model
Use male SPF rat (7 age in week).Using sufficient pad to amass gauge (Unicom) measures.Tuberculin syringe (1ml) is full of the suspension (hereinafter referred to as adjuvant) of the liquid paraffin that comprises 6mg/ml mycobacteria (Mycobacterium) B, and afterbody bottom transdermal administration 0.05ml/ rat.In addition, reject injection site hair on every side with electronic hair scissors cutter before transdermal administration.
After using adjuvant the 14th day, the sufficient pad of measuring right lower limb and left lower limb was long-pending, and based on the long-pending foot pad edema rate of every lower limb and the total edema rate of two legs calculated of sufficient pad of using before adjuvant.
Every kind of adhesive tape preparation (2.5x2.5cm) of coated sample material (detect embodiment 1 or with reference to the tape preparation of embodiment 4, Flector adhesive tape or Mohrus adhesive tape) to cover whole right lower limb and left lower limb, once a day, continues five days.In coating rear 6 hours, cover the tape preparation that applies, in case licking, the stop thing licks preparation.
Result is presented in Fig. 2.Observe antiinflammation in the tape preparation that detects embodiment 1 and Flector adhesive tape or Mohrus adhesive tape.
The rat pain model assessment of the inflammation of (2) bringing out with beer yeast detects tape preparation
Use is measured the pain threshold of right lower limb foot pad for the gauge (Ugo Basile) of the analgesic effect of Pressure stimulation in male SD rat (5 age in week).Rat is divided into groups based on pain threshold.Be coated to every kind of adhesive tape preparation of sample material (detect embodiment 1 or with reference to the tape preparation of embodiment 4, Flector adhesive tape or Mohrus adhesive tape) on rat the next day after grouping, to cover this foot pad, then fixes with the adhesive tape of performing the operation etc.The rat of untreated fish group is only fixed with the operation adhesive tape.
After apply test sample through the regular hour after, with the normal saline solution transdermal administration of 1ml 10% beer yeast to right lower limb foot pad.After the injection beer yeast 0.5,1,2 and 3 hours, measure in the same manner the pain threshold of right lower limb, and calculate the pain threshold ratio.
Result is presented in Fig. 3.Show that the tape preparation that detects embodiment 1 has the antiinflammation identical with Flector adhesive tape or Mohrus adhesive tape.
Detect embodiment 5: assessment detects blood level in without the hair rat
About male without a hair rat (6 week age), checking at the coating position of skin of back without any damage as wound.Detect embodiment (detect for No. 1, detect for No. 14 or with reference to embodiment 1) and be coated in the back of every group of rat, and stick the dressing parcel and seal with nonwoven.After sealing 48 hours, the sample that remove to apply, and with the absorbent cotton wiping painting part position of warm water moistening.To apply the position and again seal, lick in case the stop thing is licked it.Collect blood sample from rat tail vein, and assess the blood level of etodolac by LC/MS/MS.
Result is presented in Fig. 4.Show that No. 14 detections produce than No. 1 more favourable blood level of detection.
Detect embodiment 6: the antiinflammation of the tape preparation of etodolac lignocaine salt (ionic liquid)
The foot pad edema of (1) bringing out with carrageenin is assessed the detection tape preparation
The right lower limb foot pad that uses sufficient pad to amass gauge (Unicom) measurement male SD rat (5 age in week) amasss.With animal according to the sufficient pad integration group as the acquisition of index.Approximately after 18 hours, the sufficient pad of measuring right lower limb is long-pending in fasting from grouping day.
By applying tape preparation (2.5x2.5cm 2) use test sample (No. 14 detect or Flector), covering whole right lower limb, and described preparation is further fixing with the operation adhesive tape.In addition, rat is coated with scarf, in case the stop thing is licked to completing it to be licked during urging the using of inflammatory reagent applying test sample.
From applying test sample through after certain hour, 0.1ml1% carrageenin normal saline solution transdermal administration to right lower limb foot is padded.Difference is 3,4 and 5 hours after the injection carrageenin, measures the volume of right lower limb foot pad, and based on the long-pending edema rate of calculating of sufficient pad.
Result is presented in Fig. 5.Show that the tape preparation that detects for No. 14 has the antiinflammatory effect than the antiinflammatory better effects if of Flector.
Detect embodiment 7: the tissue permeability of the tape preparation of etodolac lignocaine salt (ionic liquid)
(1) muscular tissue of Rat Right lower limb
In order to assess in vivo the drug permeability of No. 14 detections, considered to use the method for rat lower limb.Assess medicine to the permeability in muscular tissue deep by the sample concentration of measuring in the rat leg muscle.Fector (diclofenac epolamine (diclofenac Epolamine) 1.3%) is as positive control.
Will be at 4 male SD rats pruning shank detection day the previous day (5 age in week) as one group.Test sample (No. 14 detections and Flector) is applied the size of 2.5x2.5cm.The position that applies is covered with gauze, and seal with sticking the dressing parcel.From applying test sample through after certain hour, put to death animal by blood-letting under anesthesia.Then excise lower limb, separate skin and other tissue, and be determined at the drug level in muscular tissue.
Fig. 6 be presented at drug level in the tissue that obtains in time-change.Detect and Flector about No. 14, the AUC (0-24) of the tissue concentration that is calculated by this result is respectively 235 μ g/ghr and 141 μ g/ghr.Show with the AUC of Flector and compare, the tape preparation of No. 14 detections has approximately 1.7-effect doubly.
(2) muscular tissue of rat abdomen
Assess medicine at the permeability of rat abdomen muscular tissue in the mode identical with above-mentioned (1).
Will be at 4 male SD rats pruning abdominal part detection day the previous day (5 age in week) as group.Test sample (No. 14 detections and Flector) is applied the size of 3x4cm.The position that applies is covered with gauze, and seal with sticking the dressing parcel.From applying test sample through after certain hour, put to death animal by blood-letting under anesthesia.Then hara kiri, choose a part of skin that applies the position.The skin of collected parts of skin is separated with other tissue, and be determined at drug level in muscular tissue.
Fig. 7 be presented at drug level in the tissue that obtains in time-change.Detect and Flector about No. 14, the AUC (0-24) of the tissue concentration that is calculated by this result is respectively 44 μ g/ghr and 24 μ g/ghr.Show with the AUC of Flector and compare, the tape preparation of No. 14 detections has approximately 1.8-effect doubly.
Detect embodiment 8: based on the variation of the different computation organizations concentration of etodolac route of administration
Relatively infiltrate into the tissue concentration of the etodolac in rat leg muscle tissue between Orally administered and transdermal administration, and therefore prove the effect of tape preparation of the present invention.
In Orally administered situation, 4 male SD rats (5 age in week) are used as one group, and pop one's head in to force by use and take the 12mg/kg etodolac that is suspended in CMC.Dosage is fixed as approximately 1.1～1.5mg/ rat.From forcing feed through after certain hour, with animal sacrificed by exsanguination under anesthesia.Then, the excision lower limb separates skin and other tissue, and is determined at the drug level in muscular tissue and blood plasma.
In the situation of transdermal administration, with No. 14 test sample in the mode identical with detecting embodiment 6 (1) with having 6.25cm 2The adhesive tape of area is coated to shank.Adjust the coated area of sample, so that when applying 24 hours, the transdermal available quantity of etodolac is about 0.7mg/ rat.After coated sample process certain hour, with animal sacrificed by exsanguination under anesthesia.Then, the excision lower limb separates skin and other tissue, and is determined at the drug level in muscular tissue and blood plasma.
Fig. 8 be presented at drug level in the muscular tissue that obtains in time-change.Find that the drug level in muscular tissue significantly increases when transdermal administration, and it does not increase when oral using so many.And, Fig. 9 show by the drug level in blood plasma and muscular tissue in time-AUC (0-24) of change calculations.In the situation that No. 14, transdermal administration detects, when the effective dose of the etodolac of every rat is adjusted into when almost identical, prove approximately 6 times of permeability height when drug permeability when transdermal administration detects for No. 14 is than Orally administered etodolac.
Detect embodiment 9: the parallel of percutaneous absorbability between the preparation of preparation of the present invention (No. 1 detection embodiment) and patent documentation 2 (JP2005-239709A) relatively detects
In order to prove the effectiveness of preparation of the present invention, consider the parallel relatively detection between preparation of the present invention and the described etodolac tape preparation of patent documentation 2.Then, preparation has the tape preparation that No. 1 of composition (w/w%) of table 12 detects production example 2 in the tape preparation of embodiment and patent documentation 2, and uses the Franz pond to detect according to the assessment that detects embodiment 1 and carry out percutaneous absorbability.Every kind of sample is coated to rat abdomen skin, and measures etodolac Transdermal absorption (the μ g/cm after 6 hours 2).Result is presented in table 12.
[table 12]
Detect number Patent documentation 2 (production example 2) 1
Etodolac 5.0 2.4
Organic amine compound (lignocaine) 4.0 1.96
Organic solvent: propylene glycol ethyl sebacate Polyethylene Glycol 2.0 7.0 2.0 2.0
Antioxidant: BHT 1.0 1.0
Softening agent: liquid paraffin white vaseline plastibase glycerol 20.0 35.0 19.64 10.0 10.0
Viscosifier: polybutene hydrogenated petroleum resin (alcon p-100) 2.0 16.0 1.0 38.0
Elastomer: SIS 8.0 12.0
Total amount 100.0 100.0
Transdermal absorption (μ g/cm 2) 25 93
As shown in table 12, show that etodolac percutaneous absorbability that preparation of the present invention (No. 1 detect embodiment) has is approximately 4 times of etodolac percutaneous absorbability of disclosed tape preparation in patent documentation 2 production examples 2, although the concentration of the etodolac that contains is about half.
The very different reason of percutaneous absorbability is owing to such fact, that is, the proportion of composing between ethyl sebacate and Polyethylene Glycol is 1: 3.5, and (1: 2-2: 1), in other words, the content of Polyethylene Glycol is too high away from preferable range of the present invention for it.
The accompanying drawing summary
Fig. 1 be show 24 hours of etodolac concentration in blood plasma in time-figure that changes.
Fig. 2 is the figure that shows the effect of tape preparation in the adjuvant arthritis rat model.
Fig. 3 is the figure that shows the effect of tape preparation in the rat pain model of the inflammation that beer yeast brings out.
Fig. 4 is the figure that shows the concentration change in blood when tape preparation being applied to without the hair rat.
Fig. 5 is the figure that shows the effect of tape preparation in the rat model of the foot pad edema that carrageenin brings out.
Fig. 6 is presented to use the figure that the drug level in rat leg muscle tissue changes after tape preparation.
Fig. 7 is presented to use the figure that the drug level in rat abdomen muscular tissue changes after tape preparation.
Fig. 8 be show muscular tissue Chinese medicine concentration in time-figure that changes, wherein reflect the difference between the etodolac of Orally administered and transdermal administration.
Fig. 9 is the figure that shows the AUC of the drug level in muscular tissue and blood plasma, wherein reflects the difference between the etodolac of Orally administered and transdermal administration.
Industrial usability
Ionic liquid and some compositions by etodolac improve, and etodolac tape preparation of the present invention has splendid percutaneous absorbability, tissue permeability and suitable adhesion.Therefore, accelerate etodolac to the tissue permeability at pain invasion and attack position, and can provide and be effective to treat chronic pain such as chronic rheumatoid arthritis, osteoarthritis or lumbago (low back pain) etc., inflammatory disease such as periarthritis humeroscapularis or tenosynovitis (thecitis) etc., neck-shoulder-arm (cervico-omo-brachial) syndrome, the DDS preparation of operation or wound pain etc.

Claims (7)

1. comprise the tape preparation of the ionic liquid of etodolac, it is characterized in that
A) molar salt such as etodolac and lignocaine formation,
B) add organic solvent, wherein pure and mild ethyl sebacate is with 1: 2-2: the ratio of 1 (w/w%) is mixed, and described alcohol is propylene glycol or 1,3 butylene glycol,
C) comprise gelled hydrocarbon, vaseline and liquid paraffin as softening agent, and
D) comprise tackifier resins, wherein said tackifier resins is at least a of the free following group that forms of choosing: polybutene, hydrogenated petroleum resin and terpene resin.
2. tape preparation according to claim 1, wherein said alcohol is propylene glycol.
3. tape preparation according to claim 1, wherein said gelled hydrocarbon is the plasticising hydrocarbon gels.
4. tape preparation according to claim 1 wherein comprises the etodolac of 1-5 (w/w) %.
5. tape preparation according to claim 1, wherein said pure and mild ethyl sebacate adds with the ratio (w/w%) of 1: 1.
6. tape preparation according to claim 1, wherein said tackifier resins is terpene resin.
7. tape preparation according to claim 1, wherein said alcohol is propylene glycol; And described tackifier resins is terpene resin.
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JP4620168B2 (en) 2011-01-26
AU2008334222B2 (en) 2013-07-18
KR20100093577A (en) 2010-08-25
JPWO2009075094A1 (en) 2011-04-28
EP2233138B1 (en) 2014-07-23
CA2708233C (en) 2015-11-03
CA2708233A1 (en) 2009-06-18
AU2008334222A1 (en) 2009-06-18
EP2233138A4 (en) 2013-05-29
US8697096B2 (en) 2014-04-15
KR101547115B1 (en) 2015-08-25
CN101896179A (en) 2010-11-24
EP2233138A1 (en) 2010-09-29
WO2009075094A1 (en) 2009-06-18
US20100280090A1 (en) 2010-11-04

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